Prolonged survival without posttransplant immunosuppression in a large animal model

Background. T cells that receive T-cell antigen receptor signals but do not undergo mitosis become unresponsive to subsequent antigenic stimulation. This can be achieved by antigen presentation to T cells in the absence of critical costimulatory signals from antigen-presenting cells (APC) or in the presence of the antiproliferative drug rapamycin. In mice, peritransplant infusion of adherent APC-depleted splenocytes, which do not provide costimulatory signals to T cells in vitro, leads to T-cell unresponsiveness in vivo and specifically prolongs the survival of skin grafts that express the major histocompatibility complex (MHC) molecules expressed by the transfused cells. Our goal was to determine whether in vivo infusion of adherent APC-depleted donor peripheral blood mononuclear cells (PBMC), with or without rapamycin, induces prolonged kidney allograft survival in a large animal model. Methods. MHC homozygous inbred miniature swine (SLA(cc)) were transfused with dendritic cell-monocyte-depleted (G10-passed) PBMC (2.5 x 10⁸ cells) from MHC disparate SLA(dd) donors, with and without three peritransfusion injections of rapamycin (0.25 mg/kg/day intramuscularly) the day before, the day of, and the day after the transfusion. SLA(cc) recipients received on SLA(dd) kidney transplant 6 days later. No posttransplant immunosuppression was given. Results. In contrast to donor-specific whole blood transfusions, which uniformly resulted in sensitization and hyperacute rejection (less than 1 day), renal allograft survival in animals that received a transfusion of G10-passed PBMC from their eventual kidney donor was similar (mean, 8.1 ± 4.6 days) to untreated controls (mean, 7.8 ± 5.0 days). Pretransplant rapamycin alone also had no effect on survival (mean, 7.7 ± 8.1 days) versus controls. The combination of G10-passed blood and peritransfusion rapamycin, however, increased survival significantly (mean, 27.3 ± 10.4 days) (p = 0.01 versus untreated recipients or recipients of only G10-passed PBMC; p = 0.03 versus recipients of rapamycin alone). Conclusions. Pretransplant transfusion with costimulator-deficient donor PBMC plus peritransfusion rapamycin treatment, but neither alone, prolongs renal allograft survival in pigs without posttransplant immunosuppression. This strategy, once optimized, may be applicable to human transplant tolerance.